Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, Faridabad, 121001, India.
CSIR-Institute of Genomics and Integrative Biology, Delhi, 110007, India.
Sci Rep. 2017 Aug 18;7(1):8789. doi: 10.1038/s41598-017-08584-9.
Stringent regulation of antiviral signaling and cellular autophagy is critical for the host response to virus infection. However, little is known how these cellular processes are regulated in the absence of type I interferon signaling. Here, we show that ATF3 is induced following Japanese encephalitis virus (JEV) infection, and regulates cellular antiviral and autophagy pathways in the absence of type I interferons in mouse neuronal cells. We have identified new targets of ATF3 and show that it binds to the promoter regions of Stat1, Irf9, Isg15 and Atg5 thereby inhibiting cellular antiviral signaling and autophagy. Consistent with these observations, ATF3-depleted cells showed enhanced antiviral responses and induction of robust autophagy. Furthermore, we show that JEV replication was significantly reduced in ATF3-depleted cells. Our findings identify ATF3 as a negative regulator of antiviral signaling and cellular autophagy in mammalian cells, and demonstrate its important role in JEV life cycle.
严格调控抗病毒信号和细胞自噬对于宿主应对病毒感染至关重要。然而，目前对于在缺乏 I 型干扰素信号的情况下这些细胞过程如何被调控知之甚少。在这里，我们发现 JEV 感染后 ATF3 被诱导，并且在缺乏 I 型干扰素的情况下，它在小鼠神经元细胞中调控细胞抗病毒和自噬途径。我们已经鉴定了 ATF3 的新靶标，并表明它结合到 Stat1、Irf9、Isg15 和 Atg5 的启动子区域，从而抑制细胞抗病毒信号和自噬。与这些观察结果一致，ATF3 耗尽的细胞表现出增强的抗病毒反应和强烈的自噬诱导。此外，我们发现 JEV 复制在 ATF3 耗尽的细胞中显著减少。我们的研究结果确定了 ATF3 作为哺乳动物细胞中抗病毒信号和细胞自噬的负调节剂，并证明了它在 JEV 生命周期中的重要作用。
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